Vascular anomalies are congenital dysregulation of vascular development and growth, and consist of a wide spectrum of disorders, including infantile hemangioma. Although infantile hemangioma is common and can cause severe physical and functional impairment for the child, the pathogenesis of this disease is poorly understood. Several angiogenic regulators of hemangioma have been identified. However, little is known regarding the signaling mechanisms that regulate hemangioma development by these factors. Hemangioma cells have high levels of activated Akt, a key regulator of vascular growth. There are 3 known Akt isoforms, and the diverse biological outcomes of Akt signaling may be due in part to the different functions of these isoforms. Our long-term goal is to understand the molecular mechanism of growth factor signaling pathways in the regulation of vascular development and growth. The objective of this proposal is to unravel the biological roles of Akt isoforms in hemangioma development. Our Specific Aims are: (1) to investigate the opposing functions of Akt1 and Akt3 in hemangioma, and (2) to determine the role of retinoblastoma binding protein 4 in mediating the function of Akt3. This work will contribute to our fundamental understanding of key signaling pathways in angiogenesis, and open new therapeutic options for children with complex hemangiomas by targeting critical pathways driving hemangioma growth. PUBLIC HEALTH RELEVANCE: This proposal will investigate the molecular pathways that drive infantile hemangioma growth. Understanding these important pathways may uncover potential therapeutic targets that can be blocked by chemical inhibitors, and provide better and more effective therapy for problematic hemangiomas. This research may also have a broad impact on angiogenesis-based therapy for other diseases, such as diabetes and cancer.